Background

Terahertz pulsed imaging (TPI) was first introduced in 2007 to non-destructively measure the coating thickness of pharmaceutical tablets. Ever since then, there has been a concerted research effort throughout the PSSRC to further develop and exploit this technique for improving the quality of pharmaceutical coatings and to shed light on the intricacies behind the pharmaceutical tablet coating process.

A notable example of previous work is the use of TPI to monitor the growth of the coating layer during the coating process as an offline technique [1]. The technology was further developed as an inline modality, where unlike the more established techniques such as near-infrared and Raman spectroscopy, TPI could measure coating thickness of individual tablets directly without chemometric models and was able resolve the tablet-to-table thickness distribution inside the coating drum during the coating process [2]. This makes the terahertz technique a unique tool to investigate the microstructure of pharmaceutical tablets as discussed in a previous research highlight.

Validation and Application

In TPI the only material dependent variable that needs to be calibrated in order to measure absolute film thickness is the refractive index of the coating material. The refractive index at terahertz frequencies is different to that at visible frequencies and while it is possible to measure it using terahertz spectroscopy it is important to validate these measurements using an independent technique. In an effort to further demonstrate the applicability of TPI, the method was validated with x-ray microtomography [3] to confirm the assumption that the refractive index is constant, within acceptable error, across the tablet surface for quantifying the absolute coating thickness (Figure 1).

TPI was also demonstrated to quantify active coating processes with active coatings up to 500 µm thick [4]. The applicability of TPI was further shown to work hand in hand with existing techniques, especially as a reference technique in the development of chemometric coating models for in-line Raman spectroscopy of process monitoring and quantification of functional coats [5].

In order to bring users up to speed when using TPI in the context of quantitative pharmaceutical tablet measurement and data analysis, a recent paper [6] presented an extensive discussion on the relevant parameters that need to be controlled so as to not fall into the trap of misinterpreting the TPI measurements. Of a particular mention in this context is the case where active coating is applied to tablets. Interestingly, the refractive index of the active coating was found to change in response to certain process conditions leading to measurement uncertainties when determining the absolute coating thickness. By comparing the content measurements as measured by an HPLC assay and the TPI coating thickness measurements it was possible to establish an excellent correlation between the TPI coating thickness measurement and the drug content in the coating (Figure 2).

Process Understanding

A high level of intra-tablet and inter-tablet coating uniformity are desired attributes in the pharmaceutical film coating process. This is especially the case for tablets receiving functional coats such as sustained release formulations, where a high level of coating variability can potentially undermine the efficacy of the eventual drug product. Even though these attributes are well sought after in the industry, achieving them realistically may prove to be rather difficult.

To date, only a handful of investigations have aimed to identify the process conditions that reliably lead to a reduction in coating thickness variability. TPI, owing to its relatively high spatial resolution, has shown to be a suitable tool for quantifying active coating thickness uniformity of tablets coated under varying process conditions [7, 8]. In particular, using design of experiments (DoE) covering a wide range of realistic coating process conditions for process parameters such as drum load, drum rotation speed, spray rate, spray pressure and coating duration, TPI was used to non-destructively identify and optimise the critical process parameters for an active coating process (Figure 3 and 4). Specifically, it was found that low drum load, high drum rotation speed and long coating durations are factors that could improve intra-tablet and inter-tablet uniformity. Even though a low spray rate was shown to be beneficial for inter-tablet coating uniformity, the same setting would be counter-productive in reducing the level of intra-tablet coating uniformity.

One immediately obvious advantage of the TPI technique for the analysis of active coating processes in this context is the speed and ease of measurement compared to an HPLC content assay: no sample preparation is required, no solvents are used and need to be disposed of and each measurement is completed in well under one hour.

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Outlook

In light of recent developments, TPI has further proven to be a robust technology in the field of pharmaceutics with particular advancements made in investigating active coating processes. While the relative immaturity and stability limitations of the technology are barriers for industry-wide adoption, TPI has shown tremendous potential in studying the coating uniformities non-destructively that otherwise would have been difficult to perform, if not impossible, with the existing popular techniques. Future implementations of the TPI as an in-line tool can effectively resolve the inter-tablet inhomogeneities during the coating operation as previously shown [2] and real-time information can be acquired for in-depth process understanding leading to greater control of the process for the production of higher quality dosage forms.

PSSRC Facilities

The group of Dr Axel Zeitler at Cambridge has extensive experience with terahertz technology. The group has a number of custom made THz spectrometers as well as its own commercial TPI coating imaging system (Teraview TPI imaga 2000) and complementing technology to investigate dosage form microstructure, such as a Skyscan X-ray microtomography system.

Professor Peter Kleinebudde’s group in Dusseldorf has a range of film coating equipment and process experience that can be used to simulate realistic process conditions during pharmaceutical film coating. In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Copenhagen, Ghent and Lille.

Introduction

The inter-tablet coating uniformity is a critical quality attribute in active coating processes. In this project an active coating process is performed in order to produce a fixed dose combination of a sustained release formulation in the tablet core and an immediate release dose in the coating layer. The tablet cores consist of a push-pull osmotic system containing nifedipine as API (Adalat GITS). They are coated with Candesartan cilexetil as a second API. As the inter-tablet coating uniformity is a critical quality attribute to comply with regulatory requirements, the purpose of this work is to enhance the process understanding and to optimize the coating process with regard to the coating uniformity. Besides experimental investigations, PAT tools such as Raman spectroscopy [1] and terahertz pulsed imaging [2] have been applied to study this active coating process. In recent years, numerical simulations of coating processes have been gaining interest as analytical tool [3]. The discrete element method (DEM) in particular is suitable to simulate the tablet motion [4]. In this project, both experimental and numerical analysis of an active coating process is combined to investigate the influence of different process parameters with respect to the optimization of the coating uniformity.

DEM simulations

Using the DEM approach, the trajectories of individual particles (in this case tablets) can be computed. The basis of the calculation is Newton’s second law, which states that the acceleration of an object is given as the net force acting upon the object divided by the mass of the object: a = F / m. Knowing the forces of a particle of given mass, the current acceleration can be calculated. From this, the velocity and position of the particles after a small time interval (time-step) is ascertained by numerical integration. An analogous treatment gives the angle and angular velocity. The calculation is straightforward as long as tablets do not collide, however, this will inevitably occur. In the DEM approach the collisions of all particles with each other or the wall are tracked. If a collision is detected, the involved particles will overlap slightly; based on this a repulsive force (contact force) is calculated. To accurately calculate these mechanical contact forces, material and interaction properties of the tablets are required.

http://www.youtube.com/watch?v=b4CiikSoOeA

Application of the run-time spray modeling. The small blue spheres are the spray drops moving towards the tablet bed. When a drop hits a tablet, the coating mass gets increased, shown as an increasing red coloring of individual tablets. Load is 3.5 kg, rotation speed is 18 rpm. The process is shown at half speed.

Material properties

Measurements of important material properties which are needed as input for the DEM simulation were carried out. Young’s modulus, the coefficient of restitution as well as the coefficients of friction were determined experimentally. It was found that the direct measurement of the coefficients of friction is possible, but the obtained values were not representative for the process. Therefore, the dynamic angle of repose of a tablet bed in a rotating drum was investigated both experimentally and in DEM simulation [5]. By comparing the results from both, it was possible to determine the coefficients of friction as they appear in the rotating drum. For the experimental coating studies, a Bohle BFC 5 lab drum coater was used.

Spray modelling

With the knowledge of the material properties from measurement and calibration, DEM simulations of the tablet motion in the drum were made. However, at this point such simulations only include tablets, and neglect the spray per se. Therefore, new methods to simulate spray processes had to be implemented. Different approaches were tested; it was shown that the best performance was given by a combination of two complementary methods [6]. First, a representation of the spray was included in the DEM simulations themselves. Second, the output data of prior simulation runs were investigated using a post-processing algorithm. The second depends on already existing data and therefore parameters such as drum rotation speed are fixed, but it is extremely fast if different spray settings (e.g., change the number of nozzles) are examined. DEM investigations were done for two scales of pan coaters (BFC 5 and BFC 50, Bohle).

http://www.youtube.com/watch?v=pB9dLxTN9Po

DEM Simulation of tablets in a Bohle BFC 5 lab coater. A load of 3.5 kg tablets of standard round biconvex shape is filled in, approximated by a glued-sphere approach. They are colored to show the axial (front/back) mixing. Rotation speed is 18 rpm, the time span shown equals to 50 s process time, the video is therefore almost in real time.

Application

With the measurements and developed methods, the active coating process can be investigated in detail. A statistical experimental plan was set up using the Design-of-Experiment (DoE) methodology. The DoE was then executed via experiment as well as DEM simulations. The main factors that were changed were rotation speed, pan load, and spray rate. After the process, the content uniformity of the API in the coating layer was assessed by calculating the coefficient of variation (CV) of the API between different tablets. Experimentally, this was done by performing HPLC analysis; in simulation, the spray modules explained above provide the required information on the coating mass on the single tablets.

By this, it was possible to investigate the influence of process parameters on the coating uniformity, and to study how the process can be optimized with respect to uniformity as well as process time. A decrease in spray rate and an increase in the rotation speed increased the coating uniformity which is consistent with results from previous studies. A complex interaction between pan load, tablet movement and the fraction of sprayed tablets was seen. The results lead to a not only qualitative, but quantitative assessment of the influences.

{gallery}dem_coating{/gallery}

Outlook

First comparisons of the experimental and simulation results show agreeing trends, however, this will be investigated in detail. To get an even deeper insight into the tablet movement, at the moment high-speed video imaging experiments are conducted; these will also pose an additional possibility for the validation of the DEM simulation.

PSSRC Facilities

The research group of Professor Peter Kleinebudde in Düsseldorf is working on solid dosage forms and pharmaceutical processes like roll compaction / dry granulation, extrusion and coating. Recent topics of the focus group “Coating / Films” are pellet layering in different kinds of processing equipment, scale up of such processes, active coating on tablets, PAT with Raman spectroscopy and terahertz pulsed imaging, simulation and experimental verification of coating processes in drum coaters and solvent film casting of orodispersible dosage forms.

The simulation work presented here is done in the group “Modeling and Prediction” working under Professor Johannes Khinast at the Technical University of Graz, which has comprehensive experience in the investigation of tablet coating using DEM.

Terahertz Pulsed Imaging

Since 2007 when terahertz pulsed imaging (TPI) was first developed to non-destructively measure the coating thickness of pharmaceutical tablets there has been intense research in the PSSRC into how this technique can help improve the quality of pharmaceutical coatings and thus make controlled release technology based on coatings of single dosage forms attractive to industry.

Measurement Principle

The measurement principle of TPI is very simple [1]: a pulse of THz radiation is focused on the surface of the coated tablet. Due to its ability to penetrate polymer materials a part of the THz pulse penetrates into the coated tablet while the remaining part of the pulse is reflected from the tablet surface due to the change in refractive index at the interface of air and coating surface. The part of the THz pulse that penetrated into the tablet undergoes subsequent reflections whenever others is a change in refractive index, such as at each interface between different coating layers. The measurement principle is similar to radar or ultrasound techniques.

The penetrative power together with the direct contrast mechanism due to the layer interface makes the TPI technique so powerful. There is no other technique on the market that can measure non-destructively at depth and resolve multiple layers at the same time without any need for chemometric calibration.

Off-line Analysis

By TPI it was possible to to reveal significant differences in coating thickness between the different surfaces of the same tablet as well as depending on the process conditions during which the tablets were coated [2]. With increasing process scale it was found that the release rate decreased for sustained-release coated tablets which was explained by the higher density of the coating layer, and thus lower diffusion coefficient, due to mechanical effects in the pilot scale coater compared to the lab scale coating process [3]. It was possible to directly correlate the TPI coating thickness measurements to the drug release rate from dissolution testing. This potentially means that for this type of coating it could be possible to predict the drug release profile of a coated tablet based on a TPI measurement of a coated tablet in applications such as real time release.

Using off-line measurements the TPI technology was used to investigate the coating process [4,5] and to carry out a detailed analysis into how coating weak spots affect the drug release [6].

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In-line Sensor Technology

Based on the potential of TPI for coating analysis a sensor was designed that was capable of in-line measurements of individual tablets within a perforated pan coater in real time under full production scale conditions [7]. The TPI approach is unique in that the sensor can directly measure the coating thickness distribution at any time point during the process. This is impossible with NIR or Raman process sensors as they are only capable of measuring a time or spatial average of the coating thickness based on chemometric models. In contrast, an individual TPI measurement takes less than 10 ms and no chemometric calibration is required.

{xtypo_quote_right}TPI is a very powerful tool to develop advanced process understanding{/xtypo_quote_right}

Process Understanding

Using a design of experiments covering a wide range of coating process conditions we have recently demonstrated how TPI can be used to identify and optimise the critical process parameters for an active coating process to achieve optimal uniformity in terms of the intra-tablet coating thickness, and hence content uniformity. Such information would be very difficult, if not impossible, to obtain with any of the other established analytical technologies. The process understanding that was developed based on the terahertz analysis can be used to explain and validate the reading from PAT sensors such as Raman process control probes.

Validation

Extensive work was carried out to validate the TPI method [8,9] as well as to use TPI to guide the development of chemometric coating models for NIR and Raman process sensors [10] as well as together with optical coherence tomography [11].

Outlook

We have demonstrated the huge potential of TPI for pharmaceutical coating analysis. It is a very attractive technology for industrial applications as well as research and development: it is fast, non-destructive, requires little calibration and can provide information on multiple coatings on curved surfaces that cannot be measured with any other technique. We are confident that TPI will establish itself as the standard analysis tool for coated solid dosage forms.

PSSRC Facilities

The group of Dr Axel Zeitler at Cambridge has extensive experience with THz technology. The group has a number of custom made THz spectrometers as well as its own commercial TPI coating imaging system (Teraview TPI imaga 2000) and complementing technology to investigate dosage form microstructure, such as a Skyscan X-ray microtomography system.

In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Düsseldorf, Copenhagen, Ghent and Lille.

{gallery}tpi_facilities{/gallery}

Videos

http://www.youtube.com/watch?v=bBLt0mEVZCgTablet imaging using a TPI imaga 2000 (TeraView Ltd. Cambridge, UK) fully automated tablet imaging system. The video is edited and shows the scan under accelerated playback. The total acquisition time for an entire tablet is about 30-60 min depending on sample size and resolution.

http://www.youtube.com/watch?v=s88UjRiZwJQVideo of the virtual THz cross-section through the coating structure of a sugar coated pharmaceutical tablet. In this representation the surface of the tablet is projected into a plane and all the coating structure is plotted relative to the surface. This representation is similar to the B-scan representation in ultrasound analysis. Note the detailed structure that can be resolved from within the sugar coating as well as the density inhomogeneities within the tablet matrix. The coating layer is clearly much thicker in the centre of the tablet compared to the edges.

http://www.youtube.com/watch?v=L7W7SRSRtH03D reconstruction of a THz pulsed imaging dataset obtained from a tri-layered pharmaceutical tablet. The dataset was acquired in reflection. The green surface is the outer surface of the tablet while the purple layers represent the interfaces between the respective layers in the tri-layered tablet. Note the penetrative power of the THz pulse (penetration of > 3 mm into the tablet, THz pulse power < 5 μW).